1. Field of the Invention
The present invention relates to compounds useful for treating cardiovascular disorders in humans or other animals, pharmaceutical compositions including said compounds and to methods for the treatment of cardiovascular disorders using said compounds and pharmaceutical compositions including said compounds. More particularly, the present invention relates to compounds, useful as antihypercholesterolemic agents and methods for reducing serum cholesterol using said compounds and pharmaceutical compositions including said compounds.
Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in Western countries. Although the etiology of atherosclerosis is multifactorial, the development of atherosclerosis and conditions including coronary artery disease, peripheral vascular disease and cerebrovascular disease resulting from restricted blood flow, are associated with abnormalities in serum cholesterol and lipid levels. The etiology of hypercholesterolemia and hyperlipidemia is primarily genetic, although factors such as dietary intake of saturated fats and cholesterol may contribute.
The bile acid sequestrants seem to be moderately effective in treating hypercholesterolemia but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
Other therapies involve the use of agents which function by limiting cholesterol biosynthesis in the cell. One such therapy involves the use of agents which inhibit the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (hereinafter HMG-CoA reductase).
2. Reported Developments
Cholesterol derivatives have been reported in the literature to exhibit hypocholesterolemic activity.
5.alpha.-cholest-8(14)-en-3.beta.-ol-15-one is reported as having significant hypocholesterolemic acitivity by Schroepfer, et al., Proc. Natl. Acad. Sci., USA 81, 6861-6865 (1984). 5.alpha.-cholest-8(14)-en-3.beta.-ol-15-one, 14.alpha.-methyl-5.alpha.-cholest-7-en-3.beta.-ol-15-one, 3.beta.-methoxy-14.alpha.-methyl-5.alpha.-cholest-7-en-15.beta.-ol, 3.beta.-methoxy-14.alpha.-methyl-5.alpha.-cholest-7-en-15.alpha.-ol, 5.alpha.-cholest-8(14)-en-3.beta.,7.xi.,15.xi.-triol, 5.alpha.-cholest-8(14)-en-3.beta.,15.beta.-diol, 5.alpha.-cholest-8(14)-en-3.beta.,15.alpha.-diol, 5.alpha.,14.beta.-cholest-7-en-3.beta.,15.beta.-diol, 5.alpha.,14.beta.-cholest-7-en-3.beta.,15.alpha.-diol, 14.alpha.-methyl-5.alpha.-cholest-7-en-3.beta.,15.beta.-diol, and 14.alpha.-methyl-5.alpha.-cholest-7-en-3.beta.,15.alpha.-diol are reported as potent inhibitors of sterol synthesis by Schroepfer, et al., J. Biol. Chem. 252 (24), 8975 (1977). 7-ketocholesterol, along with a series of steroids, is reported to suppress HMG-CoA reductase activity by Brown, et al., J. Biol. Chem. 249 (22), 7306 (1974). 7.alpha.-hydroxycholesterol, 7.beta.-hydroxycholesterol, and 7-ketocholesterol are reported to inhibit sterol synthesis by Kandutsch, et al., J. Biol. Chem. 248 (24), 8408 (1974), as are sterols derived from cholesterol by hydroxylation at the 20.alpha., 22.alpha., 22.beta., or 25 position, J. Biol. Chem. 249 (19), 6057 (1974).
Derivatives of 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one are reported in the literature as specific competitive HMG-CoA reductase inhibitors.
These derivatives include lovastatin (the active agent in MEVACOR.RTM.), which has the following structure: ##STR1## and analogs and homologs thereof.
4-Hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, and the corresponding ring-opened hydroxy acids, described as analogs of lovastatin and related compounds and which contain an aminoalkyl or substituted aminoalkyl group on the 6-position of the polyhydronaphthyl moiety, described as having antihypercholesterolemic properties, are reported in U.S. Pat. No. 4,857,546. Compounds described as semi-synthetic analogs of compactin, mevinolin, hydroxylated compactin and hydroxylated mevinolin and the dihydro and tetrahydro analogs thereof which possess a specifically substituted 8'-ester acyl moiety are reported in U.S. Pat. No. 4,661,483. Antihypercholesterolemic compounds described as 6(R)-[2-(8'-acyloxy-2'-methyl-6'-methyl (or hydrogen)-polyhydronaphthyl-1')-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-ones and their hydroxy acid form are reported in U.S. Pat. No. 4,444,784.
Trans-6-[2-[aryl and arylalkylbicyclo[a.2.b]alk(en)yl]alk(en)yl]-3,4,5,6-tetrahydro-4-hydroxy-2 H-pyran-2-ones and the corresponding ring-opened hydroxy acids, are reported as HMG-CoA reductase inhibitors, U.S. Pat. No. 4,904,692, as are trans-6-[(2-aryl substituted cycloalkenyl and substituted cycloalkyl)alkenyl and alkyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones and the corresponding ring-opened hydroxy acids, U.S. Pat. Nos. 4,863,957, 4,900,754, and 4,939,143, trans-6-[(2-aryl substituted cycloalkadienyl) alkenyl or alkyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones and the corresponding ring-opened hydroxy acids, U.S. Pat. No. 4,892,884, and trans-6-[(2-aryl substituted spirocyclic-1,3-dien-1-yl)alkenyl or alkyl]-3,4,5,6-therahydro-4-hydroxy-2H-pyran-2-ones and the corresponding ring-opened hydroxy acids, U.S. Pat. No. 4,904,691.
6-[(2-oxabicyclo[4.3.0]non-7-yl)alkyl]-4-hydroxy-2H-pyran-2-ones are reported as HMG-CoA reductase inhibitors, Jpn. Kokai Tokkyo Koho JP 01 68,367 [89 68,367].
The present invention relates to novel steroid compounds possessing hypocholesterolemic properties.